Chapman S

References (14)

Title : Non-quaternary oximes detoxify nerve agents and reactivate nerve agent-inhibited human butyrylcholinesterase - Amitai_2021_Commun.Biol_4_573
Author(s) : Amitai G , Plotnikov A , Chapman S , Lazar S , Gez R , Loewenthal D , Shurrush KA , Cohen G , Solmesky LJ , Barr H , Russell AJ
Ref : Commun Biol , 4 :573 , 2021
Abstract : Government-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood-brain barrier (BBB). There remains an urgent need for the development of next generation OPNA therapeutics. We have developed two high-throughput screening (HTS) assays using a fluorogenic NA surrogate, O-ethyl methylphosphonyl O-4-methyl-3-cyano-coumarin (EMP-MeCyC). EMP-MeCyC detoxification and EMP-BChE reactivation screening campaigns of ~155,000 small molecules resulted in the identification of 33 nucleophile candidates, including non-quaternary oximes. Four of the oximes were reactivators of both Sarin- and VX-inhibited BChE and directly detoxified Sarin. One oxime also detoxified VX. The novel reactivators included a non-quaternary pyridine amidoxime, benzamidoxime, benzaldoxime and a piperidyl-ketoxime. The VX-inhibited BChE reactivation reaction rates by these novel molecules were similar to those observed with known bis-quaternary reactivators and faster than mono-quaternary pyridinium oximes. Notably, we discovered the first ketoxime reactivator of OP-ChEs and detoxifier of OPNAs. Preliminary toxicological studies demonstrated that the newly discovered non-quaternary oximes were relatively non-toxic in mice. The discovery of unique non-quaternary oximes opens the door to the design of novel therapeutics and decontamination agents following OPNA exposure.
ESTHER : Amitai_2021_Commun.Biol_4_573
PubMedSearch : Amitai_2021_Commun.Biol_4_573
PubMedID: 33990679

Title : Lung damage following whole body, but not intramuscular, exposure to median lethality dose of sarin: findings in rats and guinea pigs - Chapman_2019_Inhal.Toxicol__1
Author(s) : Chapman S , Lazar S , Gez R , Rabinovitz I , Yaakov G , Grauer E
Ref : Inhal Toxicol , :1 , 2019
Abstract : Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxicity which includes hyper-salivation, respiratory distress, tremors, seizures, and death. Here we focused on the characterization of the airways injury induced by direct exposure of the lungs to sarin vapor and compared it to that induced by the intramuscularly route. Materials and methods: Rats were exposed to sarin either in vapor ( approximately 1LCT50, 34.2 +/- 0.8 microg/l/min, 10 min) or by i.m. ( approximately 1LD50, 80 microg/kg), and lung injury was evaluated by broncho-alveolar lavage (BAL). Results and discussion: BAL analysis revealed route-dependent effects in rats: vapor exposed animals showed elevation of inflammatory cytokines, protein, and neutrophil cells. These elevations were seen at 24 h and were still significantly higher compared to control values at 1 week following vapor exposure. These elevations were not detected in rats exposed to sarin i.m. Histological evaluation of the brains revealed typical changes following sarin poisoning independent of the route of administration. The airways damage following vapor exposure in rats was also compared to that induced in guinea pigs. The latter showed increased eosinophilia and histamine levels that constitutes an anaphylactic response not seen in rats. Conclusions: These data clearly point out the importance of using the appropriate route of administration in studying the deleterious effects of volatile nerve agents, as well as the selection of the appropriate animal species. Since airways form major target organs for the development of injury following inhalation toxicity, they should be included in any comprehensive evaluation of countermeasures efficacy.
ESTHER : Chapman_2019_Inhal.Toxicol__1
PubMedSearch : Chapman_2019_Inhal.Toxicol__1
PubMedID: 31359796

Title : Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes - Lazar_2016_Toxicol.Appl.Pharmacol_310_87
Author(s) : Lazar S , Egoz I , Brandeis R , Chapman S , Bloch-Shilderman E , Grauer E
Ref : Toxicol Appl Pharmacol , 310 :87 , 2016
Abstract : Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80mug/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h. In all brain regions tested, bax mRNA decreased 1h post exposure followed by an increase 24h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous "first response" mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention.
ESTHER : Lazar_2016_Toxicol.Appl.Pharmacol_310_87
PubMedSearch : Lazar_2016_Toxicol.Appl.Pharmacol_310_87
PubMedID: 27639427

Title : Novel bifunctional hybrid small molecule scavengers for mitigating nerve agents toxicity - Amitai_2016_Chem.Biol.Interact_259_187
Author(s) : Amitai G , Gez R , Raveh L , Bar-Ner N , Grauer E , Chapman S
Ref : Chemico-Biological Interactions , 259 :187 , 2016
Abstract : The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3-10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 x 102 vs. 0.2 x 102 M-1min-1, respectively, 37 degrees C). These hybrids inhibited AChE reversibly, IC50 = 16-48 muM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 mumol/kg in rats and 144, 203 and >506 mumol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs.
ESTHER : Amitai_2016_Chem.Biol.Interact_259_187
PubMedSearch : Amitai_2016_Chem.Biol.Interact_259_187
PubMedID: 27129421

Title : Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium - Ma_2010_Nature_464_367
Author(s) : Ma LJ , van der Does HC , Borkovich KA , Coleman JJ , Daboussi MJ , Di Pietro A , Dufresne M , Freitag M , Grabherr M , Henrissat B , Houterman PM , Kang S , Shim WB , Woloshuk C , Xie X , Xu JR , Antoniw J , Baker SE , Bluhm BH , Breakspear A , Brown DW , Butchko RA , Chapman S , Coulson R , Coutinho PM , Danchin EG , Diener A , Gale LR , Gardiner DM , Goff S , Hammond-Kosack KE , Hilburn K , Hua-Van A , Jonkers W , Kazan K , Kodira CD , Koehrsen M , Kumar L , Lee YH , Li L , Manners JM , Miranda-Saavedra D , Mukherjee M , Park G , Park J , Park SY , Proctor RH , Regev A , Ruiz-Roldan MC , Sain D , Sakthikumar S , Sykes S , Schwartz DC , Turgeon BG , Wapinski I , Yoder O , Young S , Zeng Q , Zhou S , Galagan J , Cuomo CA , Kistler HC , Rep M
Ref : Nature , 464 :367 , 2010
Abstract : Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective.
ESTHER : Ma_2010_Nature_464_367
PubMedSearch : Ma_2010_Nature_464_367
PubMedID: 20237561
Gene_locus related to this paper: fusox-a0a1d3s5h0 , gibf5-fus2 , fusof-f9f2k2 , fusof-f9f3l6 , fusof-f9f6t8 , fusof-f9f6v2 , fusof-f9f132 , fusof-f9f781 , fusof-f9fd72 , fusof-f9fd90 , fusof-f9fem0 , fusof-f9fhk2 , fusof-f9fj19 , fusof-f9fj20 , fusof-f9fki8 , fusof-f9fmx2 , fusof-f9fnt4 , fusof-f9fpy4 , fusof-f9fvs6 , fusof-f9fwu0 , fusof-f9fxz4 , fusof-f9fzy5 , fusof-f9g2a2 , fusof-f9g3b1 , fusof-f9g5h7 , fusof-f9g6e6 , fusof-f9g6y7 , fusof-f9g7b0 , fusof-f9g797 , fusof-f9g972 , fusof-f9ga50 , fusof-f9gck4 , fusof-f9gd15 , gibze-a8w610 , gibze-b1pdn0 , gibze-i1r9e6 , gibze-i1rda9 , gibze-i1rdk7 , gibze-i1rec8 , gibze-i1rgs0 , gibze-i1rgy0 , gibze-i1rh52 , gibze-i1rhi8 , gibze-i1rig9 , gibze-i1rip5 , gibze-i1rpg6 , gibze-i1rsg2 , gibze-i1rv36 , gibze-i1rxm5 , gibze-i1rxp8 , gibze-i1rxv5 , gibze-i1s1u3 , gibze-i1s3j9 , gibze-i1s6l7 , gibze-i1s8i8 , gibze-i1s9x4 , gibze-q4huy1 , gibze-i1rg17 , fuso4-j9mvr9 , fuso4-j9ngs6 , fuso4-j9niq8 , fuso4-j9nqm2 , gibze-i1rb76 , gibze-i1s1m7 , gibze-i1s3z6 , gibze-i1rd78 , gibze-i1rgl9 , gibze-i1rjp7 , gibze-i1s1q6 , gibze-i1ri35 , gibze-i1rf76 , gibze-i1rhp3 , fusc1-n4uj11 , fusc4-n1s9p6 , gibf5-s0dqr2 , gibm7-w7n1b5 , fusof-f9g6q0 , gibm7-w7n497 , fusox-x0bme4 , gibm7-w7mcf8 , gibm7-w7mak5 , fusox-x0a2c5 , gibm7-w7mum7 , fusox-w9iyc7 , gibm7-w7maw6 , gibm7-w7msi0 , gibm7-w7luf0 , gibm7-w7msa3 , gibm7-w7mna8 , gibm7-w7n8b7 , gibm7-w7n564 , fusox-w9jpi0 , gibm7-w7ngc3 , gibm7-w7m4v6 , gibm7-w7m4v2 , gibm7-w7lt61 , gibm7-w7mly6 , gibm7-w7ncn3 , fusox-w9ibd7 , fusof-f9fnm6 , gibm7-w7n526 , gibza-a0a016pda4 , gibza-a0a016pl96 , gibm7-w7muq1 , fusof-f9gfd3 , gibm7-w7mt52 , gibze-i1rjb5 , gibf5-s0ehu3 , fusox-w9hvf0 , gibze-i1rkc4 , gibm7-w7mv30 , gibze-a0a1c3ylb1 , fuso4-a0a0c4diy4 , gibm7-w7n4n0 , gibze-gra11 , gibze-fsl2 , gibf5-fub4 , gibf5-fub5 , gibf5-fus5 , gibm7-dlh1

Title : Prophylaxis against organophosphate poisoning by sustained release of scopolamine and physostigmine - Meshulam_2001_J.Appl.Toxicol_21 Suppl 1_S75
Author(s) : Meshulam Y , Cohen G , Chapman S , Alkalai D , Levy A
Ref : J Appl Toxicol , 21 Suppl 1 :S75 , 2001
Abstract : Protection efficacy of continuous prophylactic administration of physostigmine and scopolamine against sarin-induced toxicity was evaluated previously in guinea pigs. The present study in large animals used Beagle dogs, that serve as an animal model with cholinergic sensitivity similar to that of humans. Pretreatment with physostigmine salicylate and scopolamine hydrochloride at dose rates of 2.5 and 1 microg x kg(-1) x h(-1), respectively, was administered via Alzet mini-osmotic pumps. At the time of exposure, the physostigmine salicylate concentration in plasma was 0.7 ng x ml(-1) and the scopolamine hydrochloride concentration was ca. 0.2 ng x ml(-1), both of which are levels known to be well tolerated in humans. Whole-blood cholinesterase inhibition was 15-20%. This regimen conferred full protection against 2.5 x LD50 i.v. of sarin. Albeit the high-dose exposure, cholinergic toxicity symptoms were mild with no convulsions. About 11-14 min following poisoning the treated animals started to walk and 15-20 min following exposure full recovery was observed and the dogs behaved normally. With higher dose rates of physostigmine salicylate and scopolamine hydrochloride, at plasma concentrations of 2.1 and 0.6 ng x ml(-1), respectively, treated dogs regained normal posture 6-10 min after exposure.
ESTHER : Meshulam_2001_J.Appl.Toxicol_21 Suppl 1_S75
PubMedSearch : Meshulam_2001_J.Appl.Toxicol_21 Suppl 1_S75
PubMedID: 11920924

Title : Reversal of presynaptic deficits of apolipoprotein E-deficient mice in human apolipoprotein E transgenic mice - Chapman_2000_Neurosci_97_419
Author(s) : Chapman S , Sabo T , Roses AD , Michaelson DM
Ref : Neuroscience , 97 :419 , 2000
Abstract : Apolipoprotein E genotype is an important risk factor of Alzheimer's disease, which is associated with the degeneration of distinct brain neuronal systems. In the present study we employed apolipoprotein E-deficient mice and human apolipoprotein E3 and apolipoprotein E4 transgenic mice on a null mouse apolipoprotein E background, to examine the extent to which distinct brain neuronal systems are affected by apolipoprotein E and the isoform specificity of this effect. This was pursued by histological and autoradiographic measurements utilizing neuron specific presynaptic markers. The results thus obtained revealed significant reductions in the levels of brain cholinergic and noradrenergic nerve terminals in young apolipoprotein E-deficient mice and no changes in brain dopaminergic nerve terminals. These cholinergic and noradrenergic presynaptic derangements were ameliorated similarly in human apolipoprotein E3 and apolipoprotein E4 transgenic mice. In the case of the cholinergic system, this resulted in complete reversal of the presynaptic deficits, whereas in the case of the noradrenergic neurons the amelioration was partial. These findings suggest that brain cholinergic and noradrenergic neurons are markedly more dependent on brain apolipoprotein E than brain dopaminergic neurons and that the isoform specificity of these effects is not apparent at a young age under non-challenged conditions.
ESTHER : Chapman_2000_Neurosci_97_419
PubMedSearch : Chapman_2000_Neurosci_97_419
PubMedID: 10828524

Title : M1 muscarinic agonists as potential disease-modifying agents in Alzheimer's disease. Rationale and perspectives - Fisher_2000_Ann.N.Y.Acad.Sci_920_315
Author(s) : Fisher A , Michaelson DM , Brandeis R , Haring R , Chapman S , Pittel Z
Ref : Annals of the New York Academy of Sciences , 920 :315 , 2000
Abstract : A cholinergic hypofunction in Alzheimer's disease (AD) may lead to formation of beta-amyloids that might impair the coupling of M1 muscarinic ACh receptors (mAChRs) with G proteins. This disruption in coupling can lead to decreased signal transduction, to a reduction in levels of trophic amyloid precursor proteins (APPs), and to generation of more beta-amyloids that can also suppress ACh synthesis and release, aggravating further the cholinergic deficiency. These "vicious cycles," a presynaptic and a postsynaptic one, may be inhibited, in principle, by M1 selective agonists. Such properties can be detected in the functionally selective M1 agonists from the AF series [e.g., project drugs, AF102B, AF150(S)]. These M1 agonists promote the nonamyloidogenic APP processing pathways and decrease tau protein phosphorylation. The effects on tau proteins suggest a link between M1 mAChR-mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule-associated protein. This may indicate a dual role for M1 agonists: as inhibitors of two "vicious cycles," one induced by beta-amyloids, and the other due to overactivation of certain kinases (e.g., glycogen synthase kinase-3, GSK-3) or downregulation of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E-knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-affinity binding site to M1 mAChRs. Except M1 agonists, there are no reports of compounds having such combined effects, for example, amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable, yet unexplored, clinical value of such compounds.
ESTHER : Fisher_2000_Ann.N.Y.Acad.Sci_920_315
PubMedSearch : Fisher_2000_Ann.N.Y.Acad.Sci_920_315
PubMedID: 11193170

Title : The involvement of the NMDA receptor complex in the protective effect of anticholinergic drugs against soman poisoning - Raveh_1999_Neurotoxicol_20_551
Author(s) : Raveh L , Chapman S , Cohen G , Alkalay D , Gilat E , Rabinovitz I , Weissman BA
Ref : Neurotoxicology , 20 :551 , 1999
Abstract : Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes in neuronal networks. This study reports on investigations designed to assess the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which acts at these receptors, and scopolamine, which does not, was determined on soman-induced alteration in rat brain functions. Administration of soman (1xLD50) to pyridostigmine pretreated rats produced seizure activity (measured by EEG monitoring) in all animals tested. Estimation of [3H]MK-801 binding to brain membranes from intoxicated rats revealed a marked decrease in Bmax value 24 but not 2 hrs following soman administration. The specific nature of these effects of soman was demonstrated by the findings that [3H]flunitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, when used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In contrast, only caramiphen abolished soman-induced modifications in NMDA/ion channel characteristics. Caramiphen displaced [3H]MK-801 bound to the NMDA/ion channel complex, possibly by interacting with the Zn2+ site whereas scopolamine did not. Moreover, caramiphen, but not scopolamine, partially protected mice from NMDA-induced lethality. Thus, it is suggested that an important component of the protective efficacy of caramiphen against organophosphate poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties.
ESTHER : Raveh_1999_Neurotoxicol_20_551
PubMedSearch : Raveh_1999_Neurotoxicol_20_551
PubMedID: 10499354

Title : Specific neurochemical derangements of brain projecting neurons in apolipoprotein E-deficient mice - Chapman_1998_J.Neurochem_70_708
Author(s) : Chapman S , Michaelson DM
Ref : Journal of Neurochemistry , 70 :708 , 1998
Abstract : Apolipoprotein E (apoE)-deficient mice provide a useful system for studying the role of apoE in neuronal maintenance and repair. Previous studies revealed specific memory impairments in these mice that are associated with presynaptic derangements in projecting forebrain cholinergic neurons. In the present study we examined whether dopaminergic, noradrenergic, and serotonergic projecting pathways of apoE-deficient mice are also affected and investigated the mechanisms that render them susceptible. The densities of nerve terminals of forebrain cholinergic projections were monitored histochemically by measurements of acetylcholinesterase activity, whereas those of the dopaminergic nigrostriatal pathway, the noradrenergic locus coeruleus cortical projection, and the raphe-cortical serotonergic tract were measured autoradiographically using radioligands that bind specifically to the respective presynaptic transporters of these neuronal tracts. The results obtained revealed that synaptic densities of cholinergic, noradrenergic, and serotonergic projections in specific brain regions of apoE-deficient mice are markedly lower than those of controls. Furthermore, the extent of presynaptic derangement within each of these tracts was found to be more pronounced the further away the nerve terminal is from its cell body. In contrast, the nerve terminal density of the dopaminergic neurons that project from the substantia nigra to the striatum was unaffected and was similar to that of the controls. The rank order of these presynaptic derangements at comparable distances from the respective cell bodies was found to be septohippocampal cholinergic > nucleus basalis cholinergic > locus coeruleus adrenergic > raphe serotonergic > nigrostriatal dopaminergic, which interestingly is similar to that observed in Alzheimer's disease. These results suggest that two complementary factors determine the susceptibility of brain projecting neurons to apoE deficiency: pathway-specific differences and the distance of the nerve terminals from their cell body.
ESTHER : Chapman_1998_J.Neurochem_70_708
PubMedSearch : Chapman_1998_J.Neurochem_70_708
PubMedID: 9453565

Title : M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice - Fisher_1998_J.Neurochem_70_1991
Author(s) : Fisher A , Brandeis R , Chapman S , Pittel Z , Michaelson DM
Ref : Journal of Neurochemistry , 70 :1991 , 1998
Abstract : Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1-selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1-selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype.
ESTHER : Fisher_1998_J.Neurochem_70_1991
PubMedSearch : Fisher_1998_J.Neurochem_70_1991
PubMedID: 9572284

Title : The effects of the acetylcholinesterase inhibitor ENA713 and the M1 agonist AF150(S) on apolipoprotein E deficient mice - Chapman_1998_J.Physiol.Paris_92_299
Author(s) : Chapman S , Fisher A , Weinstock M , Brandies R , Shohami E , Michaelson DM
Ref : Journal de Physiologie Paris , 92 :299 , 1998
Abstract : Apolipoprotein E (apoE)-deficient and control mice were treated chronically with either the acetylcholinesterase (AChE) inhibitor ENA713, or the M1 muscarinic agonist AF150(S). Both treatments reversed the spatial working memory impairment of apoE-deficient mice but they differed in their effects on the levels of brain AChE activity. AF150(S) enhanced the brain AChE activity of apoE-deficient mice and rendered it similar to that of the untreated controls, whereas ENA713 reduced the brain AChE activity of control mice but had no effect on that of apoE-deficient mice. These findings suggest that AChE inhibition and M1 muscarinic activation have similar beneficial cognitive effects on apoE-deficient mice, but that the cellular and molecular mechanisms underlying these effects differ.
ESTHER : Chapman_1998_J.Physiol.Paris_92_299
PubMedSearch : Chapman_1998_J.Physiol.Paris_92_299
PubMedID: 9789827

Title : The effects of apolipoprotein E deficiency on brain cholinergic neurons - Kleifeld_1998_Int.J.Dev.Neurosci_16_755
Author(s) : Kleifeld O , Diebler MF , Chapman S , Oron L , Michaelson DM
Ref : Int J Developmental Neuroscience , 16 :755 , 1998
Abstract : Previous studies utilizing apolipoprotein E (apoE)-deficient mice revealed distinct decreases in the levels of cholinergic synaptic markers of projecting basal forebrain cholinergic neurons and no such alterations in other brain cholinergic systems. In order to investigate the mechanisms underlying these neuron-specific cholinergic effects, primary neuronal cultures from apoE-deficient and control mice were prepared and characterized. These include basal forebrain cultures, which are enriched in projecting cholinergic neurons, and cortical cultures, which contain cholinergic interneurons. The levels of cholinergic nerve terminals in these cultures were assessed by ligand binding measurements of the levels of the vesicular acetylcholine transporter (VAChT). This revealed that basal forebrain cultures of apoE-deficient mice contain markedly lower VAChT levels (approximately 50%) than do control cultures, but that VAChT levels of the corresponding cortical cultures of the apoE-deficient and control mice were the same. Time course studies revealed that VAChT levels of the basal forebrain cultures increased with culture age, but that the relative reduction in VAChT levels of the apoE-deficient cholinergic neurons was unaltered and was the same for freshly prepared and for 96 h old cultures. These in vitro observations are in accordance with the in vivo findings and suggest that projecting basal forebrain cholinergic neurons, but not cholinergic interneurons, are markedly dependent on apoE and that similar mechanisms mediate the in vivo and in vitro effects of apoE deficiency on cholinergic function.
ESTHER : Kleifeld_1998_Int.J.Dev.Neurosci_16_755
PubMedSearch : Kleifeld_1998_Int.J.Dev.Neurosci_16_755
PubMedID: 10198822

Title : Effects of CBDP and MEPQ on the toxicity and distribution of [3H]-soman in mice - Shapira_1990_Arch.Toxicol_64_663
Author(s) : Shapira S , Kadar T , Cohen G , Chapman S , Raveh L
Ref : Archives of Toxicology , 64 :663 , 1990
Abstract : Soman poisoning presents a problem in terms of its detailed pathophysiology and its detoxification mechanism(s). The present study was designed to evaluate the role of carboxylesterases (CaE) and cholinesterase (ChE) in the distribution and detoxification of soman in vivo. Mice were injected (i.v.) with 0.06-1.0 LD50 of [3H]-soman, 60 min following pretreatment with either 2-O-cresyl-4H-1:2:3 benzodioxa-phosphorine-2-oxide (CBDP), which blocks CaE or 7-(methylethoxyphosphinyloxy)-1-methyl quinolinium iodide (MEPQ), which selectively inhibits intravascular ChE. One hour after [3']-soman administration animals were sacrificed and whole body autoradiography was performed. High concentrations of [3H]-soman were found in lung and kidney in control mice, and low concentrations were found in central nervous system. Pretreatment with CBDP caused a 93% decrease in radioactive labelling in the lung, and a minor decrease in overall labelling, whereas pretreatment with MEPQ did not change the distribution pattern of [3H]-soman. It is concluded that lung is a major target organ for soman detoxification and that it exerts this effect by means of enzymatic reaction with soman through the abundant amounts of CaE which are present in the lung. Intravascular ChE has little (if any) effect on the distribution and detoxification of soman in vivo.
ESTHER : Shapira_1990_Arch.Toxicol_64_663
PubMedSearch : Shapira_1990_Arch.Toxicol_64_663
PubMedID: 2090035